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1.  Amelioration of nephropathy with apoA-1 mimetic peptide in apoE-deficient mice 
Nephrology Dialysis Transplantation  2010;25(11):3525-3534.
Background. There is mounting evidence that dyslipidaemia may contribute to development and progression of renal disease. For instance, hyperlipidaemia in apolipoprotein E-deficient (apoE−/−) mice is associated with glomerular inflammation, mesangial expansion and foam cell formation. ApoA-1 mimetic peptides are potent antioxidant and anti-inflammatory compounds which are highly effective in ameliorating atherosclerosis and inflammation in experimental animals. Given the central role of oxidative stress and inflammation in progression of renal disease, we hypothesized that apoA-1 mimetic peptide, D-4F, may attenuate renal lesions in apoE−/− mice.
Methods. Twenty-five-month-old female apoE−/− mice were treated with D-4F (300 µg/mL in drinking water) or placebo for 6 weeks. Kidneys were harvested and examined for histological and biochemical characteristics.
Results. Compared with the control mice, apoE−/− mice showed significant proteinuria, tubulo-interstitial inflammation, mesangial expansion, foam cell formation and up-regulation of oxidative [NAD(P)H oxidase subunits] and inflammatory [NF-κB, MCP-1, PAI-1 and COX-2] pathways. D-4F administration lowered proteinuria, improved renal histology and reversed up-regulation of inflammatory and oxidative pathways with only minimal changes in plasma lipid levels.
Conclusions. The apoE−/− mice develop proteinuria and glomerular and tubulo-interstitial injury which are associated with up-regulation of oxidative and inflammatory mediators in the kidney and are ameliorated by the administration of apoA-1 mimetic peptide. These observations point to the role of oxidative stress and inflammation in the pathogenesis of renal disease in hyperlipidaemic animals and perhaps humans.
PMCID: PMC2980997  PMID: 20488818
atherosclerosis; chronic kidney disease; hyperlipidaemia; inflammation; oxidative stress
2.  Mitogen-Activated Protein Kinase Phosphatase-1 Deficiency Decreases Atherosclerosis in Apolipoprotein E Null Mice by Reducing Monocyte Chemoattractant Protein-1 Levels 
We previously reported that mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is necessary for oxidized phospholipids to induce monocyte chemoattractant protein-1 (MCP-1) secretion by human aortic endothelial cells. We also reported that inhibition of tyrosine phosphatases including MKP-1 ameliorated atherosclerotic lesions in mouse models of atherosclerosis.
This study was conducted to further investigate the specific role of MKP-1 in atherogenesis.
Methods and Results
We generated MKP-1−/−/apoE−/− double-knockout mice. At 24 weeks of age, the size, macrophage and dendritic cell content of atherosclerotic lesions of the aortic root were significantly lower (~-41% for lesions and macropahges, and ~-78% for dendritic cells) in MKP-1−/−/apoE−/− mice when compared with apoE−/− mice. Total cholesterol (−18.4%, p=0.045) and very low-density lipoprotein (VLDL)/ low-density lipoprotein (LDL) (-20.0%, p=0.052) cholesterol levels were decreased in MKP-1−/−/apoE−/− mice. Serum from MKP-1−/−/apoE−/− mice contained significantly lower levels of MCP-1 and possessed significantly reduced capability to induce monocyte migration in vitro. Moreover, peritoneal macrophages isolated from MKP-1−/−/apoE−/− mice produced significantly lower levels of MCP-1 when compared to peritoneal macrophages from apoE−/− mice. Furthermore, MKP-1−/−/apoE−/− mice had significantly reduced serum hydroxyeicosatetraenoic acids (HETEs) levels, which have been reported to induce MCP-1 levels.
Our results demonstrate that MKP-1 deficiency significantly decreases atherosclerotic lesion development in mice, in part, by affecting MCP-1 levels in the circulation and MCP-1 production by macrophages. MKP-1 may serve as a potential therapeutic target for the treatment of atherosclerotic disease.
PMCID: PMC3037189  PMID: 20619710
mitogen-activated protein kinase phosphatase-1; atherosclerosis; monocyte chemoattractant protein-1; monocytes
3.  Paraoxonase 2 Deficiency Alters Mitochondrial Function and Exacerbates the Development of Atherosclerosis 
Antioxidants & Redox Signaling  2011;14(3):341-351.
Increased production of reactive oxygen species (ROS) as a result of decreased activities of mitochondrial electron transport chain (ETC) complexes plays a role in the development of many inflammatory diseases, including atherosclerosis. Our previous studies established that paraoxonase 2 (PON2) possesses antiatherogenic properties and is associated with lower ROS levels. The aim of the present study was to determine the mechanism by which PON2 modulates ROS production. In this report, we demonstrate that PON2-def mice on the hyperlipidemic apolipoprotein E−/− background (PON2-def/apolipoprotein E−/−) develop exacerbated atherosclerotic lesions with enhanced mitochondrial oxidative stress. We show that PON2 protein is localized to the inner mitochondrial membrane, where it is found associated with respiratory complex III. Employing surface-plasmon-resonance, we demonstrate that PON2 binds with high affinity to coenzyme Q10, an important component of the ETC. Enhanced mitochondrial oxidative stress in PON2-def mice was accompanied by significantly reduced ETC complex I + III activities, oxygen consumption, and adenosine triphosphate levels in PON2-def mice. In contrast, overexpression of PON2 effectively protected mitochondria from antimycin- or oligomycin-mediated mitochondrial dysfunction. Our results illustrate that the antiatherogenic effects of PON2 are, in part, mediated by the role of PON2 in mitochondrial function. Antioxid. Redox Signal. 14, 341–351.
PMCID: PMC3011913  PMID: 20578959
4.  A Novel Anti-Atherogenic Role for COX-2 - Potential Mechanism for the Cardiovascular Side Effects of COX-2 Inhibitors 
Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by lipid accumulation, lipoprotein oxidation, and inflammation. Products of the cyclooxygenase (COX) pathway participate in acute and chronic inflammation. The inducible form of COX, COX-2, generates lipid mediators of inflammation that are pro-inflammatory and COX-2-selective inhibitors are potent anti-inflammatory agents. However, clinical data suggest an increased risk of cardiovascular side effects in patients using COX-2-selective inhibitors. In this paper, we sought to determine the affect of COX-2 deficiency on atherosclerosis-related lipoprotein metabolism in mice. We demonstrate that COX-2 deficiency resulted in i) accumulation of lipids in circulation and liver, ii) pro-inflammatory properties of HDL as measured by HDL’s increased reactive oxygen species (ROS) content, decreased paraoxonase 1 (PON1) activity, decreased serum apoA-1, reduced ability to efflux cholesterol and to prevent LDL oxidizability, and iii) increased TXB2 in circulation. Moreover, when placed on an atherogenic diet, COX-2 deficiency resulted in i) increased lipid deposition in the aorta, ii) a further dramatic imbalance in circulating eicosanoids, i.e. decreased serum PGI2 coupled with increased PGE2 and TXB2, and iii) a marked elevation of pro-inflammatory cytokines, TNF and IL-6. Our results suggest, for the first time, that COX-2 deficiency contributes to the pro-atherogenic properties of HDL in mice.
PMCID: PMC2701232  PMID: 17643885
atherosclerosis; cardiovascular diseases; cholesterol; COX-2; cytokines; high density lipoprotein; heart diseases; hyperlipidemia; inflammation; lipoproteins; and prostanoids

Results 1-4 (4)